Amyotrophic lateral sclerosis (ALS), known colloquially as Lou Gehrig's disease, is a heterogeneous group of progressive neurodegenerative disorders characterized by a selective loss of upper and/or lower motor neurons in the brain and spinal cord. Affected individuals demonstrate a variety of symptoms including twitching and cramping of muscles, loss of motor control in hands and arms, impaired use of the arms and legs, weakness and fatigue, tripping and falling, dropping things, slurred or thick speech and difficulty breathing or swallowing. ALS eventually results in death of the affected individual.
Generally, ALS is neuropathologically characterized by degeneration of motor neurons in the brainstem, spinal cord and cerebral cortex. Clinically, ALS is typically characterized by progressive muscle weakness, wasting and fasiculations (i.e., cramping), in conjunction with spasticity, hyperreflexia and pathological corticospinal tract findings.
Excitotoxicity and oxidative stress appear to be at least two pathogenic mechanisms that participate in motor neuron cell death in ALS (Kalra et al. (1999) J. Neurol. Sci. 165:S27–S32). Among the support for a role for excitotoxicity in ALS is the findings of elevated glutamate levels in cerebrospinal fluid of patients with ALS and changes in the number or function of glutamate receptors in the central nervous system (CNS) of patients with ALS (Rothstein et al. (1990) Ann. Neurol. 28:18–25; Shaw et al. (1995) Neurodegeneration 4:209–216; Gredal et al. (1996) J. Neurol. Sci. 143:121–125; Virgo et al. (1995) Brain Res. 676:196–204). Much support for the role of oxidative stress and reactive oxygen species in ALS has come from the discovery of mutations in the gene for superoxide dismutase (SOD1) in some familial cases of ALS (Deng et al. (1993) Science 261:1047–1051; Rosen et al. (1993) Nature 362:59–62). Motor neurons in transgenic mice expressing human mutant SOD1 have been shown to be selectively vulnerable to free radical damage (Gurney et al. (1994) Science 264:1772–1775) and oxidative changes in proteins, lipids and nucleic acids have been identified in CNS tissue from patients with ALS and in the SOD1 transgenic mice. (Ferrante et al. (1997) J. Neurochem. 69:2064–2074; Hall et al. (1998) J. Neurosci. Res. 53:66–77; Ferrante et al. (1997) Ann. Neurol. 42:326–334).
Immune dysfunction has also been proposed to be linked to ALS. For example, evidence of a cell mediated immune response was identified in ALS spinal cord. For example, helper and cytotoxic T lymphocytes and reactive microglia expressing the major histocompatibility glycoproteins HLA-A, B, C and HLA-DR were found in ALS spinal cord (McGeer et al. (1991) Can. J. Neurol. Sci. 18:376–379). Cellular infiltrates consisting mainly of T lymphocytes and macrophages were found in muscle biopsy specimens from autopsied ALS patients (Troost et al. (1992) Clin. Neuropathol. 11:115–120). Most of the T lymphocytes and macrophages surrounding the atrophied muscle fibers expressed a high level of HLA-DR indicating an activated state of the cells and suggesting a role for the cells in ALS-associated muscle atrophy. Also, Schwann cells expressing HLA-DR have been identified in the endoneurium of peripheral nerve in ALS (Olivera et al. (1994) Arq. Neuropsiquiatr. 52:493–500).
ALS is diagnosed using a variety of tests and examinations, including muscle and nerve biopsy, spinal tap, X-rays, magnetic resonance imaging (MRI) and electrodiagnostic tests, many of which involve invasive procedures or complex imaging and analysis. There remains a need for an easily accessible measure of ALS disease progression for use in monitoring of the disease as well as in evaluation of potential therapies for ALS.
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